Repairing the Kidney Endothelium via Targeted Extracellular Matrix Modifiers

通过靶向细胞外基质修饰剂修复肾内皮

基本信息

批准号：
9449094
负责人：
JASON A WERTHEIM
金额：
$ 31.6万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-15 至 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9449094
关键词：
ANGPT1 gene Address Animal Model Animals Basement membrane Binding Biocompatible Materials Biology Biomedical Engineering Blood Blood Circulation Blood Vessels Blood capillaries Blood flow Carrying Capacities Cell physiology Chemistry Chronic Disease Chronic Kidney Failure Collagen Type IV Complex Congestive Heart Failure Coronary heart disease Data Deterioration Diagnosis Dialysis procedure Diffuse Disease Disease Progression Disease model End stage renal failure Endothelial Cells Endothelium Environment Extracellular Matrix Failure Foundations Functional disorder Goals Growth Factor Heparin Heparin Binding Growth Factor Homeostasis Human Hypoxia Inflammatory Inherited Injury Investigation K-Series Research Career Programs Kidney Kidney Diseases Kidney Failure Kidney Transplantation Knowledge Lead Legal patent Length Liquid substance Maintenance Mechanics Mediator of activation protein Medicine Methods Modeling Molecular Nanotechnology Nature Nephrology Organ Pathway interactions Peptides Pericytes Permeability Physiology Population Process Protein Engineering Proteins Proteomics Publications Publishing Research Research Personnel Role Science Specificity Standardization Stroke Supporting Cell System Technology Testing Therapeutic Therapeutic Agents Tight Junctions Tissues Transgenic Model Translating Translations Transplantation United States United States National Institutes of Health Universities Urine Vascular Diseases Vascular Endothelial Growth Factors Vascular Endothelium Venous animal model development base biomacromolecule cell type human disease improved improved functioning in vivo innovation kidney repair kidney vascular structure mesangial cell migration model design mortality multidisciplinary nanomaterials new technology personalized approach podocyte prevent recruit repaired restoration scaffold solute targeted delivery tool wasting

项目摘要

PROJECT SUMMARY The renal microvasculature is the convergence point for inflammatory disorders and hypoxic injury that cause endothelial dysregulation and deterioration of the underlying extracellular matrix (ECM). Together, these changes lead to progressive kidney dysfunction and ultimately failure. The regulatory role of the microvasculature in general—and in particular the microvasculature of the kidney—extends beyond its blood carrying capacity, with global implications to total-body homeostasis. Despite development of animal models of renal vascular dysfunction, which are important components of scientific research, translation of therapeutic tools and knowledge from animals to humans is limited by inconsistent linkages between transgenic models of disease and human vascular physiology. New scientific understanding of the renal vasculature microenvironment, its ECM composition, and the interdependency of endothelial cells within it provide information to develop ex vivo models of renal microvasculature. However, bioengineered systems oftentimes oversimplify the complex, interdependent nature of renal endothelial biology and the necessary cross-talk with pericytes and stroma within the microenvironment. Despite new advances in photolithography and additive manufacturing, the tiny length scales typically found within the in vivo microvasculature cannot be replicated and thus fail to adequately recapitulate the renal microenvironment ex vivo. To address this deficiency, our multidisciplinary team developed a bio-replicative renal microvasculature that mimics the scale, ECM make-up and fluid mechanics of the normal kidney. The foundation for the scientific investigation is this vascularized scaffolding system that is supported by our published data demonstrating patent and perfusable arterial and venous circulation (Caralt et al., Am J Transplant, 2015) with strict control of hydrodynamics (Uzarski, et al., Tissue Eng Part C Methods, 2015) that together result in a bio-replicative ‘test rig’. This platform provides unique opportunities to manipulate the ECM microenvironment with new technologies that unlock cellular function. To enable such an investigation, we developed Targetable ECM Modifiers (TEMs), a new biomaterial delivery system based upon our preliminary and published data (Jiang, et al. Biomacromolecules, 2016) demonstrating ability to discriminately target and shuttle bioactive agents to specific ECM sub-components. Our hypothesis is that endothelial repair leading to vascular restoration can be controlled by delivering bioactive materials to the matrix with specificity to influence endothelial cells at ECM interfaces. Our investigation is supported by data showing a 7-fold enrichment of growth factors within ECM scaffolds accessed by TEMs, compared to soluble factors delivered free in solution, leading to maintenance of an ex vivo vascular endothelium for 28 days where none developed in its absence. This investigation is further enabled by a multidisciplinary team of collaborators in bioengineering, nanotechnology, peptide chemistry and nephrology to tailor the ex vivo renal vasculature with a panel of TEMs to develop testing platforms to study disease and therapies to repair renal vascular injury and reverse kidney disease.

项目摘要肾脏微脉管系统是导致炎症性疾病和低氧损伤的收敛点内皮失调和基础细胞外基质（ECM）的确定。在一起，这些变化导致肾脏功能障碍，最终导致失败。微脉管系统的调节作用通常，尤其是肾脏的微脉管系统，超出了其血液承载能力，对全体体内稳态产生了全球影响。尽管发展了肾血管的动物模型功能障碍是科学研究的重要组成部分，治疗工具的翻译和从动物到人类的知识受疾病转基因模型之间不一致的联系的限制和人类血管生理学。对肾脏脉管系统微环境的新科学理解，其 ECM组成，其中内皮细胞的相互依赖性提供了开发离体的信息肾小管模型。但是，生物工程系统通常过度简化复合物，肾脏内皮生物学的相互依赖性质以及与周内和基质的必要串扰微环境。尽管摄影和成瘾性制造业有了新的进步，但长度很小通常在体内微脉管系统中发现的量表无法复制，因此无法充分地概括了肾脏微环境。为了解决这一缺陷，我们的多学科团队开发了一种模仿正常的量表，ECM化妆和流体力学的生物复制性肾脏微举行肾。科学研究的基础是这种血管化的脚手架系统我们发布的数据证明了专利和灌注动脉和静脉循环（Caralt等，AM J 移植，2015年），严格控制流体动力学（Uzarski等人，Tissue Eng Part C方法，2015年）共同导致生物复制的“测试钻机”。该平台提供了操纵ECM的独特机会微环境具有解锁细胞功能的新技术。为了进行这样的调查，我们开发了目标ECM修饰符（TEMS），这是一种基于我们的初步的新生物材料输送系统并发布了数据（Jiang等人，生物大分子，2016年），表明了鉴别靶向和靶向的能力穿梭生物活性剂到特定的ECM子组件。我们的假设是导致的内皮修复血管恢复可以通过将生物活性材料传递给基质具有特异性来控制 ECM界面的内皮细胞。我们的投资得到了显示7倍增长的数据的支持与溶液中免费提供的实体因素相比，TEM访问的ECM支架内的因素维持离体血管内皮的28天，在不存在的情况下没有发展。这纳米技术生物工程合作者的跨学科团队进一步启动了调查，纳米技术，肽化学和肾脏科，可通过一组TEMS来量身定制离体肾脏脉管系统以开发测试研究疾病和修复肾血管损伤和反向肾脏疾病的疗法的平台。